Summary: Learning and memory formation is a complex neurological process that consists of acquisition, storage and/or retrieval of information. Hippocampus plays an essential role in formation of long term memory that requires de novo RNA and protein synthesis and that declines with advance of age. Although progresses have been made in defining the anatomic areas and elucidating the importance of synaptic plasticity in learning and memory in the past decades, the molecular mechanisms underlying learning and memory formation as well as the aging influences in this process is unknown. In an attempt to dissect the memory process at the molecular level, we used cDNA microarray to analyze the changes of rat hippocampal gene expression before and after maze training (T-stone and water maze) and between young- and old-rats. We have analyzed global gene expression profiles of hippocampus and identified genes that were up-and down regulated after maze learning as well as genes that are differentially expressed genes between young and old rats. One of learning associated genes, neuroleukin, a.k.a. autocrine motility factor (AMF)/maturation factor (MF)/phosphohexose isomerase (PHI), was studied in detail. We found that hippocampal expression of NLK and its receptor gp78 is associated with maze learning in rodents. First, mRNA levels of NLK and gp78 were significantly increased in hippocampi of male Fischer 344 rats following training in the Stone T-maze and the Morris water maze. Second, the increase in NLK and gp78 mRNA corresponded to an increase in NLK and gp78 protein levels. Third, NLK and gp78 expression in hippocampus was lower in aged rats that showed impaired learning in the Stone maze compared to young rats. Finally, NLK and gp78 proteins were highly expressed and colocalized in neurons in the CA1-CA3 areas of hippocampus, the brain region considered to undergo representational reorganization as animals navigate their environments. Thus, our results identify a novel correlation of hippocampal expression of NLK and its receptor gp78 to rodent maze learning. These findings have implications for the mechanisms underlying learning and memory formation and aging in rodents. Currently, we are characterizing the temporal changes of these genes in the course of maze learning and aging, and studying the structure and function of some selected genes.